Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth

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Abstract
The transcriptional activity of the androgen receptor (AR) is regulated by interaction with various coregulators, one of which is -catenin. Interest in the role of -catenin in prostate cancer has been stimulated by reports showing that it is aberrantly expressed in the cytoplasm and/or nucleus in up to 38% of hormone-refractory tumours and that overexpression of -catenin results in activation of AR transcriptional activity. We have examined the effect of depleting endogenous -catenin on AR activity using Axin and RNA interference. Axin, which promotes -catenin degradation, inhibited AR transcriptional activity. However, this did not require the -catenin-binding domain of Axin. Depletion of -catenin using RNA interference increased, rather than decreased, AR activity, suggesting that endogenous -catenin is not a transcriptional coactivator for the AR. The glycogen synthase kinase-3 (GSK-3)-binding domain of Axin prevented formation of a GSK-3-AR complex and was both necessary and sufficient for inhibition of AR-dependent transcription. A second GSK-3-binding protein, FRAT, also inhibited AR transcriptional activity, as did the GSK-3 inhibitors SB216763 and SB415286. Finally, inhibition of GSK-3 reduced the growth of AR-expressing prostate cancer cell lines. Our observations suggest a potential new therapeutic application for GSK-3 inhibitors in prostate cancer.